纳米混悬剂（Nano suspension）

1、纳米混悬剂（Nano suspension）Research progress of nano suspensionAuthor: Wangyu scientific research sources: literature data, click: 531, update time: 2007-4-3keyword: nanosuspension, sirolimus, aprepitant, insulinHealth net:At present, more than 40% of the drugs in the study have poor water solubility pro

2、blems, which makes the potential good varieties can not be listed or can not give full play to the curative effect. Therefore, it is urgent to solve the problem of low bioavailability of poorly soluble drugs. The commonly used solvent solubilization, cyclodextrin and emulsion technology has some lim

3、itations, such as the co solvent of organic solvents in toxicity, and drug release; the inclusion of the size of the drug molecules with special requirements; requires high drug solubility emulsion in oil phase.In 1994, Muller and other research and development of nano suspension (nanosuspensions) c

4、an better solve the above problems. The nanoparticles are dispersed in water by the stabilization of the surfactant, and stable colloidal dispersions are formed by crushing or controlling the crystallization technique. Whether it is water insoluble drugs or drugs that are difficult to dissolve in wa

5、ter and are difficult to dissolve in oil, the corresponding nano suspension can be prepared by this method. As an intermediate dosage form, the nano suspension can be further prepared as a pharmaceutical dosage form suitable for oral administration, injection or other route of administration, thereb

6、y improving the absorption and bioavailability of the drug. Moreover, nano suspension can improve the content of the drug in the preparation, and is especially suitable for oral administration and injection of large dosage and difficult soluble medicine. In addition, because the formulation does not

7、 contain the carrier and the co solvent, the injection has the poisonous side effect to be very low.Preparation characteristicsNano suspension is the colloidal dispersion system of pure drug nanoparticles. Different from the matrix type nano system in the traditional sense, nanosuspension without ca

8、rrier material, it is through the stabilizing effect of the surfactant, the drug particles of nano scale dispersion system formed in water.Because of the characteristics of nanosuspension, which reflects the unique advantages in various administration (Table 1): such as simple prescription and prepa

9、ration, is conducive to the rapid screening of active compounds to reduce the cost and improve the drug dissolution and bioavailability, without additional ingredients caused by irritating and toxic effect and low dose volume etc.Table 1 Characteristics of pharmaceutical suspensions- - - - - - - - -

10、 - - - - - - - - - - - - - - - - - - - - - -Route of administration, dosage forms, characteristics- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -The oral administration has the advantages of small particle size, increased drug absorption rate and absorption rate, and improved bioavaila

11、bilityHigh drug content, increased mucosal adhesion, prolonged gastrointestinal retention time, and reduced individual differences in absorptionFirst pass metabolism is avoided and targeted therapy can be used to treat lymphatic system diseasesInjection without carrier or cosolvent, reduced toxicity

12、, reduced dosage (especially intramuscular, subcutaneous, and intradermal)High drug content, phagocytosis by monocytes, reduced toxicity, and increased effectivenessTwain -80 was used to deposit apo E on nanoparticlesReceptors on brain endothelial cells promote brain absorptionInhaled drugs were sma

13、ll in size, targeting alveolar macrophages, increasing respiratory tract drug absorption, and reducing systemic absorption- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -PreparationThere are mainly two aspects of preparation of nano suspension, namely prescription screening and process

14、optimization. The prescription is mainly the choice of type and amount of surfactant, in order to improve the long-term stability of the product; process optimization by adjusting the production process such as pressure and cycle number and other parameters of the high pressure homogenizer, the idea

15、l particle size distribution.Screening of surfactantsIn order to prepare stable nano suspension and avoid the aggregation and increase of nanoparticles, the appropriate surfactant must be screened. Ionic and nonionic surfactants are generally available, and ionic surfactants can cause electrostatic

16、repulsion between nanoparticles. Non ionic polymers cause steric repulsion between nanoparticles. Studies have shown that the combination of two types of surfactants can lead to better long-term stability.In the preparation of nano suspension by direct homogenization method, the type and amount of s

17、urfactant only affect the long term stability of the product, and the particle size of the product is not affected.MUller was prepared by direct homogeneous buparvaquone nanosuspension, adding poloxamer formulation (poloxamer) and polyvinyl alcohol (PVA) 188, 3 months after the drug particle size di

18、d not change significantly. However, when the content of the drug is as high as 10%, 6 months later, the drug is difficult to disperse. If the hydrogel is added to the product or the product is freeze-dried, the stability of the product can be maintained for more than one year.The trace precipitatio

19、n or emulsifying preparation of nanosuspension, surfactant type and dosage can affect the formation of crystals, choose different surfactants and their ratio can be obtained with different particle size distribution of the products. Kocbek by emulsification preparation of ibuprofen nanosuspension, p

20、rescription containing 0.25% Twain -80 product size of 158.1nm containing 0.5, twelve sodium dodecyl sulfate (SDS) when the particle size is 263.2nm, poloxamer188, PVA as the stabilizer or combination of several kinds of surfactant, the particle sizes of products are the difference.Preparation proce

21、ssThe methods for preparing nano suspension include milling method, ultrasonic method and high-pressure homogenization method. The first two methods all have grinding medium or metal residue, but the metal residue of high-pressure homogenization method is low and easy to be industrialized.Direct hom

22、ogenization (direct, homogenization)Direct homogenization method is the use of high pressure homogenizer cavitation and cavitation effects, the micronized drug particles further grinding into nano scale particles, while reducing the particle size of the polydispersity (PI). The method of direct homo

23、genization can avoid the addition of organic solvent. It is suitable for drugs which are neither soluble in water nor soluble in oil, and the process has good reproducibility. Studies show that the particle size of the product is determined by the hardness of the drug itself, the pressure of the hom

24、ogenization, and the number of cycles. By adjusting the pressure and cycle times of the high-pressure homogenizer, a product of suitable particle size distribution can be obtained. With the increase of the cycle pressure, the particle size decreases, and at last it reaches a constant value, i.e., th

25、e optimum particle size. The polydispersity decreases with the increase of cycle times. But reduce the size increase of high pressure homogenization pressure and drug particle and no linear relationship, because the process of high pressure homogenization is the destruction of the drug particles is

26、not perfect crystal, the smaller the particle size, drug crystal more perfect, crushing energy required is higher. Studies have shown that the pressure of 1500bar can crush the drug into smaller crystals, while the pressure increases to 4000bar without finer crystals.Micro precipitation (microprecip

27、itation)Micro precipitation method is a method for forming nanoparticles by dissolving the drug in an organic solvent dissolved in water and then adding the liquid into the water to control the crystallization conditions. The crystallization process involves the initial establishment of crystalline

28、nuclei and the subsequent growth of particles. The preparation of stable suspensions requires high nucleation rate but low growth rate, and the rate of both depends on the temperature, the degree of supersaturation of the drug and the rate of mechanical agitation. Therefore, the micro precipitation

29、method needs to select the proper organic solvent and its proportion, and select the appropriate crystallization temperature and stirring speed.Because micro precipitation is the process of converting the drug from a dissolved state into a suspended state, the mechanical force consumed is less than

30、that of the direct homogenization method, and is suitable for drugs with poor stability. However, due to the use of organic solvents in the preparation process, the problem of residual organic solvents may occur and may result in changes in the particle size of the drug when the organic solvent is r

31、emoved.Emulsion homogenization (lipid, emulsions)The emulsification homogenization method is to prepare the drug into O/W nanoemulsion firstly, then control the precipitation of the drug in the droplet and prepare the nano suspension. The drug is dissolved in an organic solvent and insoluble in wate

32、r (such as ethyl acetate, three acetic acid esters of glycerol and chloroform); then the medicine liquid is added to an aqueous solution containing a surfactant, using high shear mixing to form colostrum, and then use the high pressure homogenizer will further homogenization for nano colostrum milk,

33、 finally nanoemulsion added to a large number of water, the organic solvent phase to aqueous phase diffusion, and the precipitation of drug nanoparticles. The better particle size distribution can be obtained when the drug is precipitated and combined with a high pressure homogenizer. Paclitaxel alb

34、umin nanoparticles (Abraxane) have been listed in the United States by this method.Physical and chemical property evaluationWhen the solid particle size less than 1 2 m, the solubility of particles by the influence of particle size, the solubility of small particles, and the solubility of small part

35、icles, which leads to small particles and large particles gradually dissolve gradually become larger, the phenomenon known as Ostwald ripening phenomenon (Ostwald ripening). In order to prevent this phenomenon, it is necessary to select appropriate prescription to increase the physical stability of

36、the nano suspension, and optimize the preparation process to ensure that the final product has a narrow size distribution. Besides,In order to study the release properties of drug suspensions, the crystal shape and release rate of drugs should be investigated.Particle size and polydispersityResearch

37、 shows that in addition to the surfactant, the particle size distribution is an important factor affecting the stability of nanosuspension, therefore in the process of R & D nanosuspension, decided the success of prescription must first examine the grain size and its distribution, and the accelerate

38、d test, the influence of temperature and mechanical force on the particle size and distribution effect.According to the different characteristics of the nano suspension, a variety of techniques can be used to determine particle size and polydispersity. Proton correlation spectroscopy (PCs) can detec

39、t 3nm 3 m in the range of particles, is commonly used detection particle size and polydispersity (PI 0.3 has better stability) instrument; laser diffraction (LD) fast detection speed, can detect larger particles or aggregation of nanoparticles (detection range is 0.02 2000 m), of which 99% of the da

40、ta on particle sensitive, has important significance in injection detection. In addition, large numbers of particles can also be detected by Kurt counting in the preparation of injectable suspensions.Nonionic surfactant and Zeta potentialFor nano suspensions, the repulsion between particles is also

41、beneficial to the long-term stability of colloidal dispersions. If a single use of ionic surfactants, then achieve the lowest Zeta potential for the stability of about + 30mV; but the combined use of ionic and nonionic surfactant, even if the Zeta potential is lower than the critical value, but also

42、 has good physical stability, because the nonionic surfactant with particle steric repulsion effect enough, the Zeta + 20mV can reach as long as the potential.Preparation, crystal shape and appearance studyIf the drug has polymorphs, then different polymorphs affect the release rate and efficacy of

43、the drug. At present, differential scanning calorimetry and X-ray diffraction are often used to determine the crystalline state of the drug. In addition, electron microscopy can be used to observe the morphology of the nano suspension.In the preparation of nano suspension agent, the appropriate inhi

44、bitor can be added according to the requirement to control the core drug in the amorphous state. The general is adding a water soluble substance such as Miglyol is very low, it combined with drugs in reducing the interfacial tension of drug particles, while the formation of dense interface on the su

45、rface of the drug, reduce the internal diffusion of drug molecules to the aqueous phase, thereby inhibiting the Ostwald ripening phenomenon, the particle internal stability of amorphous.Saturated solubility and dissolution rateRegardless of the route of administration, the solid nanoparticles in the

46、 nanoparticles must be dissolved into molecular form before they can act as therapeutic agents, while the rate of formation of the drug molecules depends on the dissolution rate of nanoparticles. The dissolution rate of different suspensions can be measured by dialysis method and dissolution method

47、in proper dissolution medium. According to Ostwald- Freundlich equation and Noyes-Whitney equation, increasing the saturation solubility of nanoparticles can improve the dissolution rate of drugs, thus further enhancing the diffusion and absorption of drugs in the gastrointestinal tract. The determi

48、nation method of dialysis and traditional saturated solubility (the drug solution under the condition of constant temperature stirring or shaking until the dissolution equilibrium) with suspension can determine the saturated solubility of nanoparticles in nano agent. In addition, depending on the si

49、ze of the drug, ultrafiltration or direct filtration can be used to determine the solubility of the drug.Application exampleIt often takes decades for a pharmaceutical technology to be transformed into an actual product, and a nano suspension is available in just a few years. The first nano crystal patent is at the beginning of 90s by Nanosysterms company (now Elan) applicat